The present invention relates to conjugates having specific utility as depots for pharmaceutically active substances.
Providing drug depots for sustained-release action is essential for efficient treatment of patients which require a steady administration of specific pharmaceutically active substances, especially if the drug is desired to be applied inside the body. A prerequisite for an adequate drug depot is that the release of the pharmaceutically active substance from such a depot is controllable by specific retardation processes. This implies that the pharmaceutically active substance has to be connected to the depot matrix either in a reversible or an irreversible way.
The matrix to which the pharmaceutically active substance is bound should not only have an affinity to the active substance but also have biocompatible properties. Preferably, such depot matrices are biodegradable within the body of the patient so that no further treatment of the patient for removing the emptied depot is necessary.
Because of its advantageous biological properties especially fibrin gels have been proposed as preferred drug depot matrices (see e.g. AT 369 900). Fibrin gels are easy to prepare, have good biocompatibility and their biological degradation inside the body can be easily regulated. However, due to the hydrated and wide porous structure of fibrin, diffusion of pharmaceutically active substances occurs with a rate much too fast for most purposes even if the fibrin gel is highly cross-linked by excess addition of its natural cross-linking effector, factor XIII.
In preliminary experiments carried out for the present invention it could be shown that different proteins, such as xcex2-Galactosidase are completely released from a fibrin gel within three days or even less.
It has therefore been proposed to covalently link bioactive factors to a fibrin network by linking a transglutaminase substrate domain to a bioactive factor using factor XIIIa activity (WO98/43686). However, covalent binding of the drug of interest to the fibrin network may result in binding too strong to allow sufficient release of the drug to the patient. Also not all drugs do allow covalent binding; moreover, a stability problem for fibrin might arise because cross-linking sites are taken away by the transglutaminase substrates involved. The presence of transglutaminase is essential for this reaction.
It is therefore an object to provide a drug depot having satisfactory biocompatibility and a half-life in the patient life which may efficiently be regulated.
It is a further object of the present invention to provide for an alternative drug depot based on fibrin, especially without altering the active substance or using enzymatic activity for the linkage.
Another object of the present invention is to provide a drug depot with efficient retardation capacity of the biologically active substance to be administered to a patient over a prolonged period of time compared to the release time of this drug by diffusion from a standard fibrin gel.
These objects are solved by a fibrin/fibrinogen binding conjugate comprising
a fibrin/fibrinogen binding moiety,
a substance capturing moiety capable of reversibly
binding to a pharmaceutically active substance, and
a pharmaceutically active substance,
wherein said fibrin/fibrinogen binding moiety is bound to said substance capturing moiety.
With the conjugate according to the present invention the affinity of binding partners to fibrin or fibrinogen are used to link binding partners of pharmaceutically active substances to a fibrin gel. Due to these fibrin or fibrinogen binding moieties, the conjugates are bound efficiently enough to the fibrin matrix so that elution of the pharmaceutically active substance is not possible by simple diffusion but mainly dependent on the affinity of the fibrin/fibrinogen binding moiety to fibrin and on the binding affinity of the substance capturing moiety to the pharmaceutically active substance.
The binding of the fibrin/fibrinogen binding moiety to the substance capturing moiety can be covalently, e.g. via linkers as known from the state of the art, or by electrostatic forces.
The term xe2x80x9cfibrin/fibrinogen binding moietyxe2x80x9d relates to a binding moiety which is capable of binding to fibrin or to fibrinogen and fibrin. It is essential that the binding capacity is at least present for the fibrin and it is preferred if this binding capacity is also given for the fibrinogen molecule. For the latter case it is then possible to form the fibrin gel with fibrinogen molecules which are already xe2x80x9cloadedxe2x80x9d with the conjugates according to the present invention to allow a homogeneous forming of the drug depot and a homogeneous distribution of the conjugate according to the present invention (and therefore the drug) throughout the fibrin drug depot.